Department of Evolutionary Biology, University of Siena, 53100 Siena, Italy.
J Exp Med. 2011 Jun 6;208(6):1317-30. doi: 10.1084/jem.20101558. Epub 2011 May 16.
The Bordetella pertussis adenylate cyclase toxin (CyaA) assists infection by potently suppressing the host immune response. Although CyaA effectively targets T lymphocytes, its putative receptor on these cells is unknown. Here, we show that CyaA binds to T cells via the β₂ integrin LFA-1 in its active conformation. CyaA clusters with LFA-1 at the immune synapse (IS), from which it induces the premature disengagement of LFA-1 concomitant with the dissipation of talin, which tethers the integrin to the underlying actin cytoskeleton. The CyaA-induced redistribution of LFA-1 was cAMP- and protein kinase A (PKA)-dependent. These results not only identify LFA-1 as a CyaA receptor on T cells but unveil a novel mechanism of immunosuppression whereby the toxin parasitizes its interaction with LFA-1 to inhibit signaling at the IS through the local production of cAMP. The data also provide novel insights into the role of cAMP/PKA signaling in controlling the dynamics of the IS.
百日咳博德特氏菌腺苷酸环化酶毒素（CyaA）通过强烈抑制宿主免疫反应来辅助感染。尽管 CyaA 能有效地靶向 T 淋巴细胞，但这些细胞上的假定受体尚不清楚。在这里，我们表明 CyaA 通过其活性构象中的β₂整合素 LFA-1 与 T 细胞结合。CyaA 在免疫突触（IS）处与 LFA-1 聚集，从该处诱导 LFA-1 的过早脱离，同时耗散将整合素固定在下面的肌动蛋白细胞骨架上的 talin。CyaA 诱导的 LFA-1 重分布依赖于 cAMP 和蛋白激酶 A（PKA）。这些结果不仅确定了 LFA-1 是 T 细胞上的 CyaA 受体，而且揭示了一种新的免疫抑制机制，其中毒素通过利用其与 LFA-1 的相互作用，通过局部产生 cAMP 来抑制 IS 处的信号转导。这些数据还为 cAMP/PKA 信号在控制 IS 动力学中的作用提供了新的见解。
